The purpose of this research was to investigate the mechanism of radiometal retention in normal organs. The reduction of radiometal concentration in normal organ enhances the visualization of target lesions and has become more important in recent years when monoclonal antibodies labeled with beta emitting radionuclides such as Y-90 were administered for cancer therapy. To investigate the mechanism of radiometal retention in hepatocytes, we have conjugated galactose molecules to MoAb T101 (IgG2) and radiolabeled this galactosylated MoAb with In-111 using either cyclic DTPA dianhydride (cDTPA) or 2-p-isothiocyanatobenzyl-6-methyl-DTPA (1B4M) as a bifunctional chelator. These two conjugates were than radiolabeled with In-111 and injected iv into mice. These injectates were taken up quantitatively by the liver within 10 min. However, the cDTPA conjugate was retained longer in the liver than the 1B4M conjugate (55% vs 20% ID at 44 hr). During this time, the radiometabolite was excreted similarly into urine (23%) and feces (17%) for the cDTPA conjugate. For the 1B4M conjugate, the radiometabolite was excreted primarily into feces (68%) rather than urine (8%). Size exclusion HPLC analysis of both the gall bladder content and the supernatant from the liver homogenate showed two peaks, the first (35%) with the retention time (Rt) identical to IgG and the second (65%) with Rt similar to free In-111 1B4M at 3 hr post injection for the 1B4M conjugate, indicating that this metabolite is readily excreted through the biliary system. In contrast, for the cDTPA conjugate, the small DTPA-like metabolite was the major radioindium component (>90%) in the liver homogenate as early as 3 hr postinjection but the cumulative radioindium activity in feces was only 17% at 44 hr, indicating that the metabolite from the cDTPA conjugate does not clear readily through the biliary system. This study indicates that an increase in lipophilicity of the chelating agent enhances the biliary excretion of the metabolite, thereby decreasing the concentration of the radioindium in liver.